Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis

Summary

Multicenter, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for patients with sepsis-induced hypotension. The aim of the study is to determine the impact of a restrictive fluids strategy (vasopressors first followed by rescue fluids) as compared to a liberal fluid strategy (fluids first followed by rescue vasopressors) on 90-day in-hospital mortality in patients with sepsis-induced hypotension.

Timeline

Start

2018-03-07

Primary completion

2022-05-10

Completion

2022-08-24

Publications

• Jorda A, Gelbenegger G, Shapiro NI, Douglas IS, Whitman C, Chen Z, Hippensteel JA, Kamphuis LA, Flick RJ, Harhay MO, Caldwell E, Zeitlinger M, Jilma B, Iwashyna TJ, Hough CL, Auriemma CL. Effects of an early restrictive versus liberal fluid strategy on long-term patient-centered outcomes in sepsis-induced hypotension: an open-label, randomized controlled trial. Am J Respir Crit Care Med. 2026 Jul 1;212(7):1510-1521. doi: 10.1093/ajrccm/aamag154.
• Oshima K, Yan B, Tao R, Amorim G, Di Gravio C, McMurtry SA, Burke RC, Nam Y, Nikolli I, Kravitz MS, Stephenson D, Issaian A, Hansen KC, D'Alessandro A, Douglas IS, Self WH, Lindsell CJ, Leroux C, Ringor A, Matthay MA, Schildcrout JS, Shapiro NI, Schmidt EP. Plasma chondroitin sulfate predicts the effectiveness of fluid resuscitation strategies in patients with sepsis. J Clin Invest. 2026 Feb 3;136(7):e202480. doi: 10.1172/JCI202480. eCollection 2026 Apr 1.
• Oshima K, Di Gravio C, Yan B, McMurtry SA, Burke R, Levoir LM, Kravitz MS, Stephenson D, Issaian A, Hansen KC, D'Alessandro A, Douglas IS, Self WH, Lindsell CJ, Schildcrout JS, Schmidt EP, Shapiro NI. Endothelial Glycocalyx Degradation in Sepsis: Analysis of the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) Trial, a Multicenter, Phase 3, Randomized Trial. Ann Am Thorac Soc. 2025 Sep;22(9):1382-1393. doi: 10.1513/AnnalsATS.202501-012OC.
• Jorda A, Douglas IS, Staudinger T, Heinz G, Bergmann F, Oberbauer R, Sengolge G, Zeitlinger M, Jilma B, Shapiro NI, Gelbenegger G. Fluid management for sepsis-induced hypotension in patients with advanced chronic kidney disease: a secondary analysis of the CLOVERS trial. Crit Care. 2024 Jul 11;28(1):231. doi: 10.1186/s13054-024-05019-6.
• National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, Brower RG, Brown SM, Exline MC, Ginde AA, Gong MN, Grissom CK, Hayden D, Hough CL, Huang W, Iwashyna TJ, Jones AE, Khan A, Lai P, Liu KD, Miller CD, Oldmixon K, Park PK, Rice TW, Ringwood N, Semler MW, Steingrub JS, Talmor D, Thompson BT, Yealy DM, Self WH. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Feb 9;388(6):499-510. doi: 10.1056/NEJMoa2212663. Epub 2023 Jan 21.
• Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, Ginde AA, Grissom CK, Janz DR, Jones AE, Liu KD, Macdonald SPJ, Miller CD, Park PK, Reineck LA, Rice TW, Steingrub JS, Talmor D, Yealy DM, Douglas IS, Shapiro NI; CLOVERS Protocol Committee and NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators. Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Ann Emerg Med. 2018 Oct;72(4):457-466. doi: 10.1016/j.annemergmed.2018.03.039. Epub 2018 May 10.

Drugs

Indications